Abstract
The rapid absorptive clearance of drugs delivered to the airways of the lungs means that many inhaled medicines have a short duration of action. The aim of this study was to investigate whether forming polar ion-pairs can modify drug absorption to slow down clearance from the airways. Salbutamol was used as a model drug and was formulated as ion-pairs in an aqueous solution with three negatively charged hydrophilic counterions: sulfate (molecular weight (MW) 142), gluconate (MW 218), and phytate (MW 736) (association constants of 1.57, 2.27, and 4.15, respectively) and one negatively charged hydrophobic counterion, octanoate (MW 166) (association constant, 2.56). All of the counterions were well tolerated by Calu-3 human bronchial epithelial cells when screened for toxicity in vitro using conditions that in silico simulations suggested maintain >80% drug-counterion association. The transport of salbutamol ion-pairs with higher polar surface area (PSA), i.e., the sulfate (PSA 52%), gluconate (PSA 50%), and phytate (PSA 79%) ion-pairs, was significantly lower compared to that of the drug alone (PSA 30%, p < 0.05). In contrast, the octanoate ion-pair (PSA 23%) did not significantly alter the salbutamol transport. The transport data for the gluconate ion-pair suggested that the pulmonary absorption half-life of the ion-paired drug would be double that of salbutamol base, and this illustrates the promise of increasing drug polarity using noncovalent complexation as an approach to control drug delivery to the airways of the lungs.
Highlights
Direct delivery of medicines to the lungs has many advantages in the treatment of respiratory diseases
The addition of sodium sulfate, sodium gluconate, and dipotassium phytate to salbutamol in solution resulted in an increase in the N−H peak at 1596 cm−1 compared to the reference peaks of C C (1616 cm−1) and CH3 (1385 cm−1) (Figure 2)
The Kcond values calculated from the salbutamol−counterion binding plots using the Fourier transform infrared (FTIR) data were 1.57 for salbutamol sulfate, 2.27 for salbutamol gluconate, 2.56 for salbutamol octanoate, and 4.15 salbutamol phytate (Figure 2)
Summary
Direct delivery of medicines to the lungs has many advantages in the treatment of respiratory diseases. Strategies to counteract the rapid lung clearance processes and prolong drug action in the airways have been proposed. Large porous particles (LPPs) possess characteristics that enable them to penetrate deeply into the lungs,[4] which bypasses the mucociliary escalator, and avoid clearance by alveolar macrophages upon deposition.[3] Loading therapeutic agents into nanoparticles[5−8] and liposomes,[9−11] which have prolonged residence in the lungs for up to 24 h,12 can retain and control drug release at the epithelial surface. Nanoparticles can Received: November 12, 2019 Revised: February 25, 2020 Accepted: February 26, 2020 Published: February 26, 2020
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